Glucose metabolism, synaptic plasticity, and oxidative stress in Alzheimer's disease Alzheimer's disease (AD) is the leading cause of cognitive disability in the United States. It affects over 5 million Americans at annual cost in excess of $150 billion. Despite the human suffering and financial burden, there are no proven therapies to stem progression of the disease. Members of this program project have provided support for the notion that alterations in brain glucose metabolism are not only highly correlated with cognitive decline in AD, but can precede symptom onset by years in those at risk. The ability of normal function to be maintained in those with diminished glucose suggests the existence of compensatory mechanisms which forestall the disease but fail over the long term. This proposal will explore the interplay of those adaptive compensatory mechanisms and the maladaptive ones that lead to cognitive decline over the long term. In preliminary studies, we have unexpectedly found that lowering glucose uptake into cultured neurons or into the hippocampus in vivo enhances activity-dependent gene expression but increases vulnerability to oxidative stress. Our overall hypothesis is that diminished glucose into neurons early in AD preserves learning and memory but creates long term vulnerability to oxidative stress and A-beta overproduction. We believe that diminished glucose leads to near term improvements in synaptic function via the deglycosylation of transcription factors, specifically CREB. Deglycosylation at serine 40 leads to recruitment of the coactivator TORC (transducer of regulated CREB), and induction of genes associated with learning and memory (CREB, BDNF) as well as mitochondrial biogenesis (PGC1?). Our aims, which integrate with all members of the PPG using differentiated human cortical neurons (Project 2) or an AD mouse model (TG19959, Projects, 3 and 4) are targeted at developing strategies to maintain the short term, beneficial effects of glucose deprivation on learning and memory while interdicting the ability of this enzyme to trigger oxidative death and increased A? production over the long term. In our last aim, we will use a novel reporter of the redox regulated transcription factor, Nrf-2 expressed in astrocytes as a strategy to identify when redox dyshomeostasis occurs in the TG19959 model of AD. We will also use this reporter to develop, with Project 4, a safer and more effective approach using an FDA approved Nrf-2 activator in combination with an FDA approved antioxidant which we predict will nullify oxidative stress while maintaining adaptive plasticity associated gene expression.Together these studies will evaluate novel targets and therapies for optimizing the adaptive effects of reducing glucose into neurons on learning and memory while minimizing deleterious consequences related to oxidative stress and bioenergetic dysfunction.